The infestation of domestic animals with blood-feeding parasites, in particular with ticks and fleas, is a considerable health problem.
Fleas are wingless insects which have a laterally compressed body and highly developed legs suitable for jumping. They are blood-sucking ectoparasites of mammals or birds. The some 2000 species listed belong to the order Siphonaptera. 
Two species of fleas are commonly encountered in Europe; they are the cat flea (Ctenocephalides felis) and the dog flea (Ctenocephalides canis) which live in the fur of the animals. The cat flea, which is the most common, is capable or reproducing on both cats and dogs. It can also attack humans and other pets; however, the cat is the main animal responsible for infestation when cats and dogs live in the same environment.
Fleas have a complex life cycle with 4 distinct stages: egg, larva, pupa and adult. They mate in the first 8 to 48 hours following acquisition by the host, after their first blood meal. The females thus begin to lay eggs 24 to 48 hours after this first blood meal. The adult flea generally lays eggs on the animal. The eggs laid on the animal do not however remain there, and fall to the ground. Under optimum conditions, the female can lay more than 25 eggs a day. She will lay several hundred eggs throughout her life. After a few days, a hairy white wormlike larva, approximately 1.5 mm long, is born. The larva feeds on organic debris, on larval remains and on dry blood defecated by the adults. The larval state lasts 1 to 3 weeks, if conditions are favorable (18° C. to 27° C. and 70% relative humidity). The larva then spins a cocoon and pupates. Normally, the pupa evolves in 1 to 2 weeks, but passage to the adult state can extend up to one year, if conditions are unfavorable. The adult flea (small and black) emerges from the cocoon when it detects vibrations, heat, or a higher concentration of carbon dioxide, which occurs when a cat, a dog . . . or a human! passes by. It then jumps onto the victim, immediately feeds on blood and rapidly grows, becoming a lighter, reddish-brown color. The adult flea lives for 6 to 12 months. It can survive for up to 2 months without food.
Flea bites cause itching in both animals and humans. The flea saliva (secreted at each bite) can also, depending on individuals, lead to immediate or delayed allergic reactions. These reactions result in various skin lesions and itching. Two types of flea-related dermatosis are distinguished: namely pulicosis and flea allergy dermatitis. While in both cases the dermatosis results from a more or less substantial infestation with fleas, only in the second case is there an associated allergic phenomenon. Flea allergy dermatitis (FAD) is the most common cause of pruritus in dogs. In France, in adult dogs, it thus represents close to half the pruritic dermatoses. Close to 80% of dogs which exhibit FAD also have atopic dermatitis, and, vice versa, two atopic dogs out of three exhibit FAD. It is therefore probable that atopic dogs are predisposed to the development of a flea allergy and that infestation with the latter is a triggering factor for atopic dermatitis. This is proof of the need for a very intensive antiflea control in atopic dogs or dogs belonging to breeds at risk. Furthermore, FAD is probably the main cause of the reappearance of pruritus in desensitized atopic dogs.
Fleas of the Ctenocephalides genus are, moreover, intermediate hosts of Dipylidium caninum, which is a parasitic worm of the small intestine of dogs and cats. The carnivore becomes infested by swallowing the parasitized fleas. This infestation can cause anal pruritis, engorgement of the anal sacs, and also dermatitis of the perineal region. It is therefore sometimes recommended to worm animals regularly in addition to combating fleas.
Flea infestations therefore represent a considerable problem for the animals which are infested and make it necessary to have suitable treatments. It is in particular advisable for the treatment to have not only an immediate efficacy (rapidity of action), but also an efficacy sustained over time (persistence) in order to avoid, on the one hand, repeat treatments and, on the other hand, any risk of infestation and/or reinfestation for a sustained period. The flea must be eliminated before it reproduces and begins to lay eggs.
There are currently various types of insecticidal treatments against fleas on the market (shampoos, powders, aerosols, collars, tablets, liquid compositions for topical application). However, not all these treatments always give complete satisfaction.
Antiparasitic shampoos constitute a good “attack treatment” in the case of massive infestations, but do not have a long-lasting effect. They treat only the adult fleas and are particularly difficult to use on cats, which do not generally appreciate baths.
Antiparasitic powders contain an insecticidal active ingredient diluted in talc. This method of application is not very effective since the talc slides along the coat and the product rarely penetrates as far as the skin. Furthermore, there is a risk that the animals will accidentally ingest the insecticidal active ingredient or the other constituents of the composition when they lick themselves. The use of powder is also not very convenient, since the application thereof can take several minutes, may not be uniform over all the animal's fur and is accompanied by pulverulent particles being given off and being inevitably inhaled by the animal and its owner even in the case of particularly meticulous application.
This type of problem is also encountered with the use of mechanical vaporizers or sprays, or of aerosols (for example, based on permethrin as active ingredient) which, furthermore, have the additional drawback of generating stress or an aggressive reaction in the animal to which it is applied, given the noise generated at the time of spraying. The compositions applied by virtue of these devices are, moreover, generally not very persistent (maximum of 1 week) and poorly water resistant.
Antiflea collars are generally quite effective in a temporary manner. However, their efficacy is essentially limited to the regions of the animal which are close to the collar (neck, nose, thorax). On the other hand, on the other parts of the animal, the efficiency of antiflea collars can be very poor, or even nonexistent. Furthermore, cats which are used to going out risk getting their collar caught on a branch or wire fencing and of hurting themselves by becoming strangled.
The systemic, in particular oral or parenteral, administration of pharmaceutical compositions already represents a certain advance, in terms of efficiency, compared with the various treatments detailed above. Quite a wide choice of preparations using various active ingredients known to have an antiflea activity is currently found on the market. In the event of an oral administration, these active ingredients are absorbed at the gastrointestinal level and find their way to the animal's blood so as to cause poisoning of the fleas during the bite. Among products of this type, mention may in particular be made of the product Capstar®, using, as active ingredient, nitenpyram (the chemical name of which is (E)-N-(6-chloro-3-pyridylmethyl)-N-ethyl-N′-methyl-2-nitro-vinylidenediamine according to the IUPAC nomenclature), as described, for example, in patent application EP 0 616 494. The Capstar® product, which is in the form of tablets for dogs and cats, has a highly rapid action. Specifically, the maximum blood concentration is reached in 30 to 120 minutes in fasting dogs and cats. However, the plasma half-life of the active ingredient is 4 hours in dogs and 8 hours in cats; 90% of the molecule being secreted in the urine in one day in dogs and in two days in cats. Thus, this product is effective for a very short period of time and it is necessary to administer it daily according to the producer's recommendations. This product also has the drawback of being in the form of tablets, the administration of which is not easy, or is even impossible, in certain relatively uncooperative, or particularly ferocious, animals.
Finally, the marketed products that are active against fleas can also be in the form of liquid compositions (pipettes) or “spot-on” solutions for the skin, that are applied very easily, in one go, topically, directly to the animal's skin, generally between the shoulder blades. By way of examples of products of this type, mention may be made of:                fipronil-based products, such as the product Frontline® Spot-On Chat et Chien, sold in France by the company Merial SAS. It is often presented as a product of choice for preventing and treating flea infestations. However, according to the producer's data, the fipronil active concentration threshold is exceeded after 24 hours over the entire body surface of the animal and it therefore has the drawback of not being very rapidly active. Moreover, the period of protection against further infestations is limited to 4 weeks and the product is not therefore very persistent;        imidacloprid-based products, such as the products Advantage® Chat and Advantage® Chien, sold in France by Bayer Pharma Division Sante Animale [Animal Health Division]. According to the producer's data, the fleas are killed within 24 hours after application of the treatment and the period of protection against further infestations is 4 weeks. Thus, the rapidity of action and the persistence of these products are not entirely satisfactory;        the combination of permethrin and imidacloprid sold under the name Advantix® by the company Bayer or else the combination of permethrin and pyriproxyfen sold under the name Duowin® Contact by the company Virbac, which both have the major drawback of being intended only for dogs since they are very toxic in cats.        
Other documents envision the topical administration of products against external parasites.
In particular, patent application EP 0 616 494, cited above, mentions the topical route among various routes of administration of 1-N-(halo-3-pyridylmethyl)-N-methylamino-1-alkylamino-2-nitroethylene derivatives; however, it is not the pathway described as being the most advantageous.
Patent application DE 198 07 633 proposes a composition for limiting the dermal development of parasitic insects in animals; this water-based composition also comprises a nicotinic acetylcholine receptor agonist or antagonist and a solvent chosen from cyclic carbonates and lactones.
Patent application EP 0 976 328 describes an agent for combating ectoparasites in animals, comprising a neonicotinoid and a solvent chosen from a glycol ether or a glycol monoalkyl ether.
Patent application WO 2004/064522 describes topical formulations combining (i) a type I or type II pyrethroid, a pyrethroid with no ester function or a natural pyrethroid, with (ii) a compound chosen from neonicotinoids, nithiazine and spinosyns.
Patent application EP 1 668 984 describes a synergistic combination, for oral or topical administration, composed of a 1-phenylpyrazole derivative, with a pesticide chosen from lactone macrolides, neonicotinoids, insect growth regulators (IGRs), pyrethroids, pyrimidines, organophosphates and amitraz.
Patent application JP 2001/0291535 describes a liquid composition for treating ectoparasites in dogs and cats, comprising a pesticide, an antioxidant and an oily solvent; said pesticide being chosen from pyrethroids, neonicotinoids, phenylpyrazole derivatives, phenylpyrrole derivatives, organophosphates and insect growth regulators.
Patent application JP 2001/0216111 describes a composition for treating the ectoparasites of pets, which is provided in the form of a suspension of a water-insoluble pesticide or of a solution of a water-soluble pesticide. The pesticides can be chosen from pyrethroids, neonicotinoids, phenylpyrazole derivatives, phenylpyrrole derivatives, organophosphates, insect growth regulators and chitin synthesis inhibitors.
However, none of these documents describes the specific use of a 1-N-(halo-3-pyridylmethyl)-N-methylamino-1-alkylamino-2-nitroethylene derivative, such as nitenpyram, topically, nor demonstrates an advantage to the topical use thereof compared with other routes of administration.
Patent application WO 00/29378, the subject of which relates to new antiparasitic compounds, even emphasizes that, when the compounds of general formula (II) which includes nitenpyram are administered topically, the efficacy thereof fades rapidly after administration, thus making it necessary to carry out frequent applications. However, it is impossible, based on this document, to determine the precise conditions for formulation and administration of the compounds of general formula (II) to which these observations correspond.